The F-domain of estrogen receptor-alpha inhibits ligand induced receptor dimerization

Yang, Jun; Singleton, David W.; Shaughnessy, Elizabeth; Khan, Sohaib A.

doi:10.1016/j.mce.2008.08.001

Cited by 38 publications

(32 citation statements)

References 24 publications

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“…A Y2H β-gal assay with ERα-LBD or ERα-LBD T594A confirmed that the F-domain C terminus controls receptor dimerization (Fig. 3C), as reported before (17). Strikingly, the T 594 A mutation, which annihilates the 14-3-3 interaction ( Fig.…”

Section: Resultssupporting

confidence: 87%

“…Receptor dimerization is an essential step in the cascade of events through which ERα modulates gene expression and therefore any changes that alter ERα dimerization will have profound effects on ERα function. After binding of ligand, ERα monomers undergo dramatic conformational changes exposing sequences required for dimerization and evidence has been presented that the carboxy terminal F domain imparts internal restraint on ER dimerization (17,37). Notably, mutations in the last few amino acids of the F domain somehow relieve the restraint on dimerization imposed by the F domain and enhance transcriptional activity (17).…”

Section: Discussionmentioning

confidence: 99%

“…The F domain is a relatively understudied part of the receptor and due to its flexibility, no structural information has been available until now (16). Analysis of F-domain truncation mutants point to an important role for the last few amino acids in receptor dimerization and transactivation activity (17).…”

mentioning

confidence: 99%

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Interaction of 14-3-3 proteins with the Estrogen Receptor Alpha F domain provides a drug target interface

Leeuwen

Pereira

Flach

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

126

180

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Estrogen receptor alpha (ERα) is involved in numerous physiological and pathological processes, including breast cancer. Breast cancer therapy is therefore currently directed at inhibiting the transcriptional potency of ERα, either by blocking estrogen production through aromatase inhibitors or antiestrogens that compete for hormone binding. Due to resistance, new treatment modalities are needed and as ERα dimerization is essential for its activity, interference with receptor dimerization offers a new opportunity to exploit in drug design. Here we describe a unique mechanism of how ERα dimerization is negatively controlled by interaction with 14-3-3 proteins at the extreme C terminus of the receptor. Moreover, the small-molecule fusicoccin (FC) stabilizes this ERα/14-3-3 interaction. Cocrystallization of the trimeric ERα/ 14-3-3/FC complex provides the structural basis for this stabilization and shows the importance of phosphorylation of the penultimate Threonine (ERα-T 594 ) for high-affinity interaction. We confirm that T 594 is a distinct ERα phosphorylation site in the breast cancer cell line MCF-7 using a phospho-T 594 -specific antibody and by mass spectrometry. In line with its ERα/14-3-3 interaction stabilizing effect, fusicoccin reduces the estradiol-stimulated ERα dimerization, inhibits ERα/chromatin interactions and downstream gene expression, resulting in decreased cell proliferation. Herewith, a unique functional phosphosite and an alternative regulation mechanism of ERα are provided, together with a small molecule that selectively targets this ERα/14-3-3 interface.T he estrogen receptor alpha (ERα) is a ligand-dependent transcription factor and the driving force of cell proliferation in 75% of all breast cancers. Current therapeutic strategies to treat these tumors rely on selective ER modulators (SERMs), like tamoxifen (TAM) (1) or aromatase inhibitors (AIs) that block estradiol synthesis (2). Although the benefits of treating hormone-sensitive breast cancers with SERMs and AIs are evident, resistance to treatment is commonly observed (3, 4). To overcome resistance, selective ERα down-regulators (SERDs) can for instance be applied that inhibit ERα signaling through receptor degradation (5, 6). Approaches that target the ERα/ DNA or ERα/cofactor interactions are explored as well (5, 7), but other essential steps in the ERα activation cascade are currently unexploited in drug design, also due to a lack of molecular understanding of the processes at hand.One such step that is crucial for many aspects of ERα functioning is ligand-driven receptor dimerization (8, 9). 17β-Estradiol (E2) association with the ERα ligand binding domain (LBD) drives large conformational changes (10) resulting in ERα dissociation from chaperones (11, 12), unmasking of domains for receptor dimerization, and DNA binding (13,14). Whereas the LBD contains the main dimerization domain (15), the extreme C-terminal domain of the receptor (F domain) imposes a restraint on dimerization (15, 16), although the regulation of this remain...

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Section: Resultssupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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Interaction of 14-3-3 proteins with the Estrogen Receptor Alpha F domain provides a drug target interface

Leeuwen

Pereira

Flach

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

126

180

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“…The functionality of this SNP is not known yet, but it seems to recruit coregulators. Yang et al suggest that the C-terminal amino acids of ERalpha (the F domain) are critical for attenuation of E2 induced receptor dimerization and transcriptional activity; the F-domain mutants showed increased receptor dimerization [47]. They also observed enhanced interaction of F domain mutants with p160 family coactivator SRC1.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor alpha polymorphisms: correlation with clinicopathological parameters in breast cancer

Anghel¹,

Raica²,

Nariţa³

et al. 2010

neo

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Polymorphisms in estrogen receptor alpha gene (ESR1) have been previously associated with breast cancer risk; however, the results were not fully consistent. Our purpose was to study interactions between common genotypes in ESR1, breast cancer risk and tumor phenotypes. 6 ESR1 single nucleotide polymorphisms (SNPs) were genotyped in 103 breast cancer patients and 90 controls using hybridization probes; the genotypes were correlated with known prognostic factors for breast cancer and 5 years-follow up data. To assess estrogen and progesterone receptors (ER, PR) and HER2/neu expressions, immunohistochemistry was performed. Our results showed that rs3798577 was significantly associated with the risk of breast cancer, the common allele C conferring susceptibility (p-trend=4x10 -5 ); rs3798577 was also correlated with PR expression (p=0.01), but not with ER expression; rs2228480 (p=0.047) and rs1801132 (p=0.02) were associated with the age at diagnosis; rs1801132 was correlated with hypercholesterolemia (p=0.003) and increased BMI (body mass index) (p=0.01); rs2234693 showed a low significant association (p=0.042) with the tumor grade; rs3798577 was correlated with disease-free survival (p=0.05), allele C conferring increased risk for relapses, but it reached not statistical significance after adjustments. In conclusions, we identified four genotypes significantly correlated with either the risk or some tumor characteristics, suggesting that the main selection criteria of the investigated SNPs (frequency and the position in modulating domains of the gene) are pertinent instruments for establish correlations between the gene structure and the tumor phenotype.

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“…23 Meanwhile, the F region of ERα is believed to negatively regulate the dimerization process, which might counteract the propensity of self-recruitment in high local concentrations. 24 Thus, it is worth a detailed examination whether the fusion of a truncated ERα consisting of the above regions exhibits improved inducing efficacy of estrogen while avoiding unexpected constitutive autocleavage in the absence of gene delivery system, our caspase-8 and estrogen receptor-based chimeric protein holds out great promise in an effective treatment of estrogen-dependent and -independent breast cancers.…”

Section: Discussionmentioning

confidence: 99%

Estrogen-induced dimerization and activation of ERα-fused caspase-8: Artificial reversal of the estrogenic hormone effect in carcinogenesis

Zhao

Zhou

Bai³

et al. 2011

Cancer Biology & Therapy

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The F-domain of estrogen receptor-alpha inhibits ligand induced receptor dimerization

Cited by 38 publications

References 24 publications

Interaction of 14-3-3 proteins with the Estrogen Receptor Alpha F domain provides a drug target interface

Interaction of 14-3-3 proteins with the Estrogen Receptor Alpha F domain provides a drug target interface

Estrogen receptor alpha polymorphisms: correlation with clinicopathological parameters in breast cancer

Estrogen-induced dimerization and activation of ERα-fused caspase-8: Artificial reversal of the estrogenic hormone effect in carcinogenesis

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